(1) Field of the Invention
The invention generally relates to an improved method of synthesis of 1-substituted azacycloalkan-2-ones and more particularly relates to an economic method of manufacturing high purity 1-dodecylazacycloheptan-2-one.
(2) Background of the Prior Art
The conventional method of preparing 1-alkyl substituted azacycloalkan-2-ones is based on the reaction of alkali salts of azacycloalkan-2-ones with alkylating agents; see, for example, L. Ruzicka, Helv. Chim. Acta 4, 472 (1921); C. S. Marvel et al., J. Org. Chem. 22, 1065 (1957); R. M. Moriarty, J. Org. Chem. 29, 2748 (1964); A. P. Swain, et al., J. Org. Chem. 18, 1087 (1953), and U.S. Pat. No.'s 3,989,815, 3,989,816, 3,991,203, and 4,112,170. In the prior art, the alkali salts of azacycloalkan-2-ones are prepared by reacting alkali metals or alkali metal hydrides with the corresponding lactams in the presence of an inert solvent under nitrogen atmosphere. This prior art method, however, is uneconomic because of the costly alkali metals or alkali metal hydrides, as well as large amounts of solvent required.
G. L. Isele et al., (Synthesis, 266, (1971)) disclose the alkylation of azacycloheptan-2-one with 1-bromobutane, benzyl chloride and 1-chlorooctadecane in the presence of dimethyl sulfoxide as the solvent and potassium hydroxide as the hydrogen halide acceptor. The authors attribute their results to a specific action of the dimethyl sulfoxide employed by them as solvent, namely to a marked promotion of the formation of the potassium salt of the lactam. In spite of its advantages when compared with older methods, this process is not suitable for commercial use on a large scale. Though the yields are adequate, the use of relatively costly potassium hydroxide, and the simultaneous use of large amounts of an expensive solvent are detrimental to its economy. Also removal of the solvent dimethyl sulfoxide from the product may pose problems if the boiling points are close.
In improving this method, U.S. Pat. No. 3,865,814 discloses that lactams, even in the absence of solvents, can be alkylated in high yields using primary alkyl or aralkyl halides and with alkali metal hydroxides as hydrogen halide acceptors. Specifically for economic reasons sodium hydroxide was preferred. However, this method requires repeated distillations and the fractions containing the product are contaminated with varying amounts of starting lactams. Thus, this method is not suitable from a commercial standpoint, especially where high purity of the alkylated lactam is essential for therapeutic applications.
During the past decade phase transfer catalysis has emerged as a technique for conducting useful synthetic reactions in heterogeneous reaction systems. Two classes of compounds are generally recognized as phase transfer catalysts: the quaternary "onium" salts and the polyethers. In the former category are found ammonium and phosphonium compounds and occasionally arsonium species as well. In the later group are found glymes, crowns, cryptands and related species. The two basic requirements of a phase transfer catalyst are that it be able to transfer one reactant from its normal phase into the normal phase of the second reactant and that the transferred reagent, once there, be available in a highly active form. Precisely how reactive the anion is depends upon the anion, the organic solvent in which the reaction is expected to occur, the amount of water present in the organic phase, the degree of association between cation and anion, concentration, temperature, and a number of other factors. Some of these factors are characteristic of the reaction or can be controlled in conventional ways but some are highly influenced by the choice of catalyst. Also, stability of the catalyst under the reaction conditions, availability of the catalyst, cost, ease of removal or recovery etc. are of importance in selection of a suitable catalyst.
J. Palacek et al., (Z. Chem., 17, 260 (1977)) disclose a method of manufacturing azacycloalkan-2-ones (5, 7 and 9 membered rings) with primary alkyl halides and aralkyl halides as alkylating agents using Benzyltriethylammonium chloride (BTEAC) as the phase transfer catalyst; however, the method produces low yields.